自然出版集团与亚太地区分子生物学联盟（A-IMBN）在3月9日出版的一期“研究亮点”（Latest Highlights）专栏上以“担负重任的小分子”为题介绍了上海药物所国家新药筛选中心科研人员对小分子化合物Boc5开展的最新研究，认为这种治疗饮食所致肥胖和2型糖尿病的干预措施具有良好前景。

文章说，由王明伟领衔的课题组最近在小鼠模型中发现一个命名为Boc5的小分子化合物可以改善肥胖及2型糖尿病。

激活胰高血糖素样肽-1受体（GLP-1R）能够改善2型糖尿病患者和动物的胰岛素敏感性和降低食欲。然而迄今为止，在临床上试验的GLP-1R激动剂都是肽类分子，难以口服给药。王明伟的团队先前已经发现在遗传性肥胖和2型糖尿病小鼠身上显示良好疗效的GLP-1R小分子激动剂Boc5可以口服。研究人员继而将治疗对象拓展到一类更能代表人类疾病的模型上，以高脂饲料喂养小鼠12周诱导肥胖后连续12周注射Boc5（每周3次），实验结果显示Boc5改善了胰岛素敏感性和血脂异常状况，与未接受治疗的肥胖小鼠相比，Boc5使体脂显著减少，脂肪肝病变减轻，血糖水平趋于正常。

研究人员认为Boc5有可能成为肥胖及其并发症有效小分子临床治疗的候选化合物。

原文出处：

PLoS ONE 5(12): e14205. doi:10.1371/journal.pone.0014205

Reversal of Obesity and Insulin Resistance by a Non-Peptidic Glucagon-Like Peptide-1 Receptor Agonist in Diet-Induced Obese Mice

Min He1,2, Haoran Su1¤a, Weiwei Gao1, Stina M. Johansson1¤b, Qing Liu1,2, Xiaoyan Wu1,2, Jiayu Liao1¤c, Andrew A. Young1¤d, Tamas Bartfai3, Ming-Wei Wang1,2,3*

Background

Glucagon-like peptide-1 (GLP-1) is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R) agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO) mice, an animal model of human obesity and insulin resistance.

Methodology/Principal Findings

DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg) for 12 weeks. Body weight, body mass index (BMI), food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, β-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of β-cell mass. Administration of Boc5 (3 mg) reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various extents by Boc5 treatment.

Conclusions/Significance

Boc5 may produce metabolic benefits via multiple synergistic mechanisms and may represent an attractive tool for therapeutic intervention of obesity and diabetes, by means of non-peptidic GLP-1R agonism.